Impulse control disorders (ICDs) are increasingly becoming an area of focus in the treatment of Parkinson's disease (PD), due to their emergence in many patients as the result of dopaminergic therapies including dopamine agonists (DAs) and less commonly, levodopa.

Epidemiologic research indicates that the main ICDs are most likely the result of chronic DA use, particularly at higher dosages, while DDS is more likely to be triggered by chronic use of shorter-acting, higher-potency dopaminergic medications including apomorphine and levodopa.1,3,4

Daniel Weintraub, MD, professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania, Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC) in Philadelphia, and co-investigator in the DOMINION study,5 told Neurology Advisor that the dopamine connection to the expression of ICDs is well established, given the strong association with dopaminergic therapy in the context of PD treatment and imaging studies of the dopamine system. “All short-acting dopamine agonists seem to have the same impact,” Dr Weintraub said, “and there is a suggestion, although not clearly established, that long-acting oral agents or patch formulations may be less likely to cause ICDs compared with short-acting agents.”

Prevalence

The reported occurrence of the primary ICDs associated with PD is extremely broad, with prevalence estimates ranging from 3.5% to 42.8%.6 The DOMINION trial4 found an estimated rate of 17% in patients with PD taking DAs, while a 2016 cross-sectional study by Vela, et al7 reported that DA treatment was associated with a 7-fold increased risk of developing an ICD in patients with early-onset PD.

The ICARUS (Impulse Control disorders And the association of neuRopsychiatric symptoms, cognition and qUality of life in ParkinSon disease) study, reported recently by Antonini, et al6 in the Journal of Neurology, Neurosurgery and Psychiatry, found the prevalence of all 4 ICD types remained stable across the 2-year study period.

ICARUS was a large-scale, prospective, multicenter observational study of the prevalence of individual ICD behaviors in a cohort of 1069 patients with PD who had been pharmacologically treated for a minimum of 6 months.5 The investigators also reported that while the prevalence of ICDs related to the use of DAs and levodopa were similar (26.7%, 64/240 vs 25%, 56/211), the combination of DAs and levodopa was associated with a higher rate of ICDs (30.1%, 179/594).6

Amygdalar Mechanisms

Impulse control disorders are thought to be related to impaired function of decisional impulsivity associated with rapid, disinhibited decision-making, rather than motor impulsivity.2 They may comprise a number of features including delay discounting (an attraction to small, immediate rewards over larger, delayed ones), reflection impulsivity (rapid decision-making), risk taking, reduced sensitivity to adverse outcomes, and response conflict.2

Jennifer Goldman, MD, MS, FAAN, of Rush Medical Center in Chicago, Illinois investigated the roots of neuropsychiatric issues in PD, including cognitive dysfunction and ICDs.7 One proposed mechanism she found was amygdalar dysfunction that could affect behavioral signals to trigger fear, anxiety, and compulsive behaviors.8,9

Known as the pain-pleasure center, the amygdala generates rapid, unconscious emotional and cognitive responses to sensory input.8,9One of the primary functions is fear modulation — evaluation of situations for the initiation of the fight-or-flight response. These subliminal fear signals are processed unconsciously using visual pathways that have been shown to overlap with emotional pathways that may heighten arousal to both real and imagined (dissociated) stimuli.8,9

The inhibitory mechanisms in the amygdala involve mostly gamma-aminobutyric acid (GABA) neurons, which are largely regulated by dopamine. “Physiological dopaminergic modulation of the amygdala's response to emotional processing follows an inverted U-shaped curve,” Dr. Goldman wrote.8,9 Affective behaviors including ICDs are then triggered in stressful situations as a result of dopaminergic disinhibition.10,11 In healthy individuals, this response was shown on magnetic resonance imaging (MRI) to be initiated in the amygdala by levodopa.12

Impulse control disorders are among the positive or “plus” symptoms of amygdalar dysfunction, believed to be triggered by D2/D3 dopaminergic overstimulation in predisposed individuals.8 An interesting physiological finding by Biundo, et al13 pointed to a potential cause of a plus dopaminergic response when they discovered significant increases in gray matter (GM) volume on MRI in the left amygdala of patients with PD exhibiting ICDs.13 These patients also demonstrated cortical thinning of the frontostriatal circuitry, along with reduced volume of the corpus collosum and nucleus accumbens.12 The investigators hypothesized that preserved amygdalar function in these individuals might put them at higher risk of ICDs when they are treated with levodopa or dopamine agonist therapies.13